Abstract

Human and all the living beings are exposed to certain chemical, physical, biological, environmental as well as occupational factors during
their day to day activities. Some of them may have adverse impact upon health including reproduction. There are reports which suggest that
deterioration of reproductive health occurs in industrialized countries in recent decades. Thus, exposure to certain synthetic chemicals and
changing life styles might be one of the cause behind the deterioration of reproductive health in recent decades.

The available data indicated that occupational/environmental exposure especially to some of the organic solvents, pesticides, metals,
plasticizers such as phthalates; ionizing and nonionizing radiations, extreme heat, stress might have adverse effects on male reproduction
and associated function which depends upon the dose, duration of exposure, age, time of exposure, and health status of exposed person,
nutrition etc. Some of the life styles factors such as tobacco smoking and chewing, excessive use of alcohol, certain illicit drugs and sedentary
life style, working in hot environment etc. may also have some impact upon male reproduction in addition to host factors. Human are exposed
to some of them simultaneously so that there may be of synergistic effects of these factors behind the cause of deterioration of reproductive
health. Hence it is difficult to pinpoint a single compound or factor responsible for the cause of declining semen quality.

There is a need for awareness among the society about the adverse effects of these factors behind the cause for the deterioration in semen
quality and associated reproductive health impairments observed in recent decades so that preventive measure can be adopted to safeguard
reproductive health.

Introduction

Reproduction is a key biologic event in human as well as for all the living
beings and any threat to reproductive health evokes significant response not
only from the scientific community but also from all walks of life including
from public media as our future is depend upon the sound reproductive health
of the parents. There are ample reports which indicated that the reproductive
health is deteriorating from the last 5-6 decades from different parts of the
world especially from industrialized /developed countries indicating the role of
industrial chemicals as well as modern sedentary life styles behind the cause of
these disorders. Human are exposed to several chemicals and life style facors
simultaneously during their day to day activities as well as during occupations
and some of them are endocrine disrupting chemicals and they act at a very low
concentration. These chemical compounds may directly have the reproductive
toxc potential or indirectly affect through their metabolic compounds or may
also have synergistic effect.

A meta-analysis published in 1992 stating a significant decline in sperm
concentration and semen volume over the period from 1938-1990 (Carlsen
et al., 1992). Thereafter several reports were published regarding deteriorating
male reproductive health from different parts of the world even though some
contagious data also existed. Jacques et al. (1995) suggested a population-wide
decline in the semen quality over the past 50 years. They measured the sperm
quality parameters in healthy fertile men during 1973- 1992 and reported that
there has been a decline in the sperm concentration, motility and percentage
of morphologically normal sperm in fertile men. Later Toppari et al. (1996)
reported that male reproductive health has worsened in many countries i.e.
Denmark, Belgium, France, and Great Britain. The incidence of testicular cancer
has increased; cryptorchidism and hypospadias also shown to be increasing.
Similar reproductive troubles occur in numerous wildlife species also. However,
there are obvious geographic differences in the prevalence of male reproductive
disorders. The growing number of reports demonstrating that environmental
contaminants and natural factors possess estrogenic activity suggests the
hypothesis that the trends in adverse male reproductive health may be, at least
in part, linked with exposure to estrogenic or hormonally active environmental
chemicals during fetal and childhood development. Later Ten et al. (2008)
reviewed the data on occupational, life style exposures and male infertility
and reported that human semen quality may be decreasing due to exposure
to environmental toxicants, occupational exposures and lifestyle factors. In
another review Queiroz and Waissmann (2006) reported that a significant
increase in the incidence of male infertility may be the result from exposure
to substances like pesticide such as DDT, linuron, and others, heavy metals
like mercury, lead, cadmium, copper, and substances from industrial uses and
residues such as dioxins, polychlorinated biphenyls (PCBs), ethylene dibromide
(EDB), phthalates, polyvinyl chloride (PVC) and ethanol can cause male infertility. The elucidation of relationship between an occupational exposure
and a reproductive health effect is almost hampered by the fact that many
adverse outcomes may be caused by multiple (work-related) factors, making
it difficult to pinpoint a specific outcome to a precise occupational exposure.
Another significant issue is that occupational exposure may only be pertinent
during specific time windows, such as shortly before conception or during
initial pregnancy (Burdorf et al., 2006). Recently, Mansour (2014) evaluated
the impact of occupational and environmental exposures on reproductive
health and suggested that there are strong and rather consistent signs that
the reproductive system is vulnerable to insult from exposure to widespread
occupational and environmental agents. Earlier Chia (2000) reported that
semen quality has deteriorated in many countries over the last few decades
and the incidence of testicular cancer has increased world-wide. A biological
possible hypothesis has suggested that man-made chemicals act as endocrine
disruptors ensuing in alteration of the development of the reproductive tract
causing the observed effects.

Owing to these, author’s laboratory engaged from the last ~ two decades to
understand the role of occupational, environmental exposure, lifestyle factors on
reproductive health. The present review is written with the view to look in to the
role of occupational, environmental and life style factors and male reproductive
health as data are accumulated steadily in recent years on these aspects.

Materials and Methods

The literature was collected through searching various websites such as
PubMed, Google, Toxnet and through books and journals pertaining to
reproductive, environmental and occupational health. The paper is divided in
to different sections based upon the occupational, environmental and life style
factors associated with reproductive health. The data are summarized with
respect to occupational and environmental exposure in Table-1, and life style
factors and reproductive health in Table-2.

Air PM10 and PM10-2.5 exposures, not PM2.5, are risk factors of semen quality

Zhou et al. (2018)

Ambient air pollution associated with oxidative stress, to which sperm are sensitive. Air pollution exposure not associated with semen quality, except sperm head parameters. Moderate ambient air pollution may not be a contributor to semen quality

The emotional stress in an IVF program negatively affects the quality of semen

Ragni and Caccamo, (1992)

Occupational Exposure and Reproductive Health
It is rational to believe that workers are exposed to higher doses
of certain chemical and physical factors during their occupation as
compared to environmental exposure. Workers are exposed to higher
doses of toxic metals, organic solvents, phthalates, pesticides, ionizing
and non-ionizing radiations and extreme heat, noise, etc. as compared
to environmental exposure. Exposures to some of these factors might
affect the male reproduction. However, it is sometime very difficult to pin
point a single chemical and/or any exogenous factors behind the cause
of reproductive impairments as workers or even general population are
exposed to a minute’s concentration of number of toxic chemicals during
day to day activities through various sources even without the knowledge
of the exposed person. The impact of this low level of exposure can only
be predicted/suspected /assessed when couple is interested to go for
pregnancy or its outcome and faces difficulty in conceiving.

Metals
Human are exposed to some of the toxic as well as essential metals from
their environments, occupations as well as through their dietary habits
and life style. Some of the metals are essentials for the certain physiological
function of the body at trace level, are known as trace element or essential
element. Reproductive dysfunction has been reported among workers
exposed to certain metals like lead, cadmium, mercury, chromium,
copper etc. at the workplace which depends upon the toxic potential of
the metal in question, exposure concentration and duration of exposure
and host factor such as age and sex. These heavy metals may affect male
reproductive function at the cellular and sub cellular levels and their effect
can be seen on semen quality, libido and male mediated reproductive
outcome. The vast experimental data are available on the toxic potential of
various heavy metals such as lead, mercury, cadmium, chromium to male
reproduction. However, the data on reproductive toxic potential of metals
on human are scanty except some judicious data on lead with regards to
male reproduction.

Mercury
Mercury compounds are present in three forms i.e. elemental, inorganic,
and organic. Exposure to mercury has the potential to affect most of the
organs of the body including reproductive system. The foremost course
of human exposure to methyl mercury (MeHg) is mostly through eating
contaminated fish, seafood, through dental amalgam etc. Recently Rice
et al. (2014) reported that mercury has profound cellular, cardiovascular,
renal, haematological, pulmonary, neurological, immunological,
endocrine, reproductive, and embryo toxic effects. Several animal studies
indicated that mercury is a male reproductive toxicant, but human studies
are scanty and inconsistence. Mercury has been implicated in male subfertility
in Hong Kong and found higher level of mercury in the hair of
sub fertile compared to the fertile male (Dickman et al., 1998). Earlier,
Ernst and Lauritsen (1991) investigated the effects of mercuric chloride
and methyl mercuric chloride on the human spermatozoa motility in vitro
and found that organic as well as inorganic mercury decreased the sperm
motility. Later, Leung et al. (2001) investigated the association between
whole blood mercury concentrations and semen quality in sub-fertile
men. The semen quality parameters and hormone profile were linked
between subjects with normal and elevated mercury level concentrations.
The semen quality parameters such as concentration of sperm, percentage
of motile sperm and morphologically normal sperm, curvilinear
velocity, average path velocity, straight-line velocity, and amplitude of
lateral head displacement were reduced in subjects with elevated blood
mercury concentrations, although the difference was statistically nonsignificant.
However, findings of Mocevic et al. (2013) do not support
that environmental mercury exposure in European and Greenlandic men
with median blood mercury concentration up to 10 ng ml−1 has negative
effects on male reproductive health. Recently, Emokpae et al. (2016) reported mean seminal plasma lead and mercury levels were significantly
higher in infertile males. Mercury and lead correlated negatively with
sperm count, total motility, progressive motility, and morphology but not
with semen volume. However, Hanf et al. (1996) could not established
positive correlation between subject with mercury concentrations in urine
and the semen quality. Equally, no such relationship could be established
between the fertility index and the number of dental amalgam fillings.
They mentioned that no evidence can be derived between the mercury
burden from dental amalgam fillings and male fertility disorders from
their study. Very recently Mínguez-Alarcón et al. (2018) found the median
hair Hg levels of the men was 0.72ppm (0.03 to 8.01ppm) and hair Hg
levels were positively related with sperm concentration, sperm count,
progressive motility, after adjusting potential confounders.

Lead
Lead poisoning has been recognised as a major public health problem
which is widely used in acid battery plant refinery, smelter, fuel combustion
industry, printing press, etc. The main source of lead contamination arises
mainly from occupation since as of now de-leaded gasoline is not sold in
most part of the world which was a major source of lead contamination.
Earlier Lancranjan et al. (1975) reported that increased levels of lead were
associated with decreased libido and an increase in semen abnormalities
in men who were exposed to lead in the workplace. It is also reported
that heavy occupational exposure to lead is sufficient to cause clinical
poisoning, may be associated with disturbances of endocrine and
reproductive functions in men (Cullen et al., 1984). Later Alexander et al.
(1998) examined the blood and semen lead concentrations in lead smelter
workers and found decline in total sperm count with increasing blood
lead concentration. Semen lead concentration was inversely significantly related to total sperm count, ejaculate volume and serum testosterone,
but not to sperm concentration. They also suggested that blood lead
concentration was more reliably associated with indicators of sperm
production than semen lead level. Later Pant et al. (2003) from Lucknow,
India measured the concentration of lead and cadmium in the seminal
plasma and found an elevation in lead and cadmium concentrations in
infertile men and there was a significant negative association of cadmium
and lead concentration with sperm concentration and sperm motility in
oligoasthenospermic men. A study from Zagreb, Croatia of reproductive
endocrine function of male industrial workers indicated that moderate
exposures to Pb (BPb<400 μg/L) can significantly reduce human semen
quality without conclusive evidence of impairment of male reproductive
endocrine function (Telisman et al., 2000). Earlier Assennato et al. (1986)
also observed sperm count suppression without endocrine dysfunction in
lead-exposed battery workers. Later Apostoli et al. (1998) also mentioned
that concentration of lead > 40 μg/dl seemed to be associated with decline
in sperm count, volume, motility, and sperm morphological alterations
and modest effect on endocrine profile. Impairment of male reproductive
function such as decreased volume of ejaculation, prolonged latency of
semen melting, reduced total sperm count and live spermatozoa, retarded
sperm activity and lowered density of seminal fluid was observed in lead
exposed male workers with Pb-B over 40 μg/dl by Xuezhi et al. (1992).
Later Erfurth et al. (2001) mentioned that a moderate exposure to lead was
associated with only minor alterations in the male endocrine function,
especially affecting the hypothalamic-pituitary axis. Recently Hosni et al.
(2013) found a significantly lower sperm motility, count in subjects with
duration of exposure was ≥15 years, but no significant difference was found
for PbB and serum levels of LH, FSH, PRL and Testosterone. Patients with
PbB ≥20 μg /dl showed a significant decline in sperm motility and elevation
in testosterone alone among all measured hormones. Earlier Chowdhury
et al. (1986) studied semen qualities in workers occupationally exposed to
lead in a printing press and reported the average lead content in blood and
seminal plasma were 42.5 μg/100 ml and 14.80 μg/100 ml, respectively
and sperm counts and percentage of motile sperm were significantly declined while abnormal spermatozoa were elevated. The levels of seminal
succinic dehydrogenase, acid phosphatase, and fructose were also found
to be significantly low. Later Robins et al. (1997) studied semen quality
and fertility potential of men employed in a lead acid battery plant and
significant associations were found between an increased percentage of
sperm with abnormal morphology and higher concentration of current
blood lead, cumulative blood lead, and duration of exposure.

Several reports have also appeared in recent decades which indicated
that lead affect the semen quality even at lower doses. Hernández-Ochoa
et al. (2005) evaluated environmental lead affects semen quality, sperm
chromatin, in view of Pb in spermatozoa (PbSpz), seminal fluid (PbSF),
and blood (PbB) as exposure biomarkers in men. About 44% subjects
showed decrease in sperm quality; sperm concentration, motility,
morphology and viability associated adversely with PbSpz, whereas semen
volume associated negatively with PbSF. However, PbB was not associated
with semen quality or nuclear chromatin condensation. These data
suggest that Pb in semen compartments is better biomarkers of low Pbexposure.
Later Awadalla et al. (2011) reported that semen quality of men
with primary infertility does not have any correlation with BLL at the cutoff
value of 20μg/dL. However, a significant reduction in haploid sperm
counts and chromatin condensation was observed. Mendiola et al. (2011)
also reported that lead and cadmium in the seminal plasma is associated
with moderate alteration of seminal parameters. In recent years more,
data appeared which indicated that lead can affect human reproduction at lower doses than reproductive toxic doses of lead reported earlier. In
addition, the effect of cadmium, lead, or manganese on male reproductive
function was examined in workers exposed to cadmium in smelters, to
lead in battery workers, or to manganese in a dry alkaline battery plant.
The likelihood of a live birth was not different between the cadmiumor
manganese-exposed workers and unexposed workers. However, the
fertility of the lead-exposed workers was deteriorated (Gennart et al.,
1992). Later Lin et al. (1996) also reported that workers with more than
five years of exposure to lead had reduced likelihood of fathering a child
as compared with a shorter duration of exposure. These studies indicated
that lead exposure might have reduced the fertility potential of male.

There are reports which indicated that lead also induces oxidative stress
and promotes the generation of hydrogen peroxide (Ni et al., 2004; Vaziri
and Khan, 2007) and reactive oxygen species. Very recently Kasperczyk et
al. (2015) investigated the relationship between environmental exposure
to lead and cytokines in seminal plasma among subjects with normal
semen profile. The total oxidant status value and the level of protein
sulfhydryl groups, activities of catalase and manganese superoxide
dismutase were significantly higher in the higher lead exposure group,
whereas the total antioxidant capacity and the activities of glutathione
reductase and glutathione-S-transferase were reduced. TNF-α and IL-7,
IL-10, IL-12 levels were also significantly higher in the high Pb exposure
group. This suggests that lead induce oxidative stress in seminal plasma
and alter antioxidant defence system. Based upon the available data it can
be concluded that Pb has reproductive toxic potential, induces oxidative
stress and impaired fertility and no safe dose can be prescribed for lead
exposure.

Cadmium
Cadmium is also a toxic heavy metal and found in ores together with
zinc, copper and lead. Cadmium is used generally in, Nickel-Cadmium
rechargeable batteries, cadmium coating, production of pigments,
cadmium alloys etc. and humans are normally exposed to either by
ingestion or inhalation. Smokers are also exposed through tobacco
smoking. Akinloye et al. (2006) estimated serum and seminal plasma
cadmium concentrations in infertile Nigerian males. The serum and
seminal plasma Cd levels were increased significantly in azoospermics
in comparison to oligozoospermic and control subjects. Earlier Chia et
al. (1992) noted the mean blood concentrations of lead, mercury, copper,
and zinc were within the normal values whereas cadmium concentration
(1.35μg/L) was much higher among subjects with no medical cause of
impaired semen quality. Asthenozoospermics subjects had significantly
higher blood cadmium levels than normozoospermic subjects. Later
Telisman et al. (2000) reported that even moderate exposures to Cd
(BCd< 10 μg/L) can significantly reduce human semen quality without
evidence of impairment of male reproductive endocrine function. Zeng et
al. (2004) concluded that oral Cd exposure is not a critical determinant of
hormone homeostasis in males, but lifestyle and biological factors, such as
age and BMI, are important. The relationship found between urinary Cd
and high T levels may be of importance for male reproductive morbidity.
Jurasovic et al. (2004) studied semen quality and reproductive endocrine
function with respect to blood cadmium in Croatian male and found the
median and range BCd values were significantly higher in smokers. After
adjusting for potential confounding variables by multiple regressions,
BCd was significantly associated with a decrease in testis size and an
increase in serum estradiol, FSH, and testosterone. Later Cheng et al.
(2011) reported that environmental toxicants, such as cadmium-induced
disruption of testicular function which is mediated primarily through its effects on the occludin/ZO-1/focal adhesion kinase complex at the bloodtestis
barrier (BTB), producing reallocation of protein at the Sertoli-Sertoli
cell interface, and leading to the BTB interruption. The destructive effects
of cadmium to testicular function are facilitated by mitogen-activated
protein kinases (MAPK) downstream, which in turn disturbs the actin
bundling and accelerates the actin-branching activity, instigating disruption of
the Sertoli cell tight junction (TJ)-barrier function at the BTB and disturbing
spermatid adhesion at the apical ectoplasmic specialization that leads to
untimely release of germ cells. Cadmium concentration was elevated, and zinc
was reduced in the seminal plasma of men with varicocele (Benoff et al., 1997).
A significant opposite relationship exists between Cd and sperm number per
ejaculum, and sperm density. Further, 8-OHdG was significantly interrelated
with Cd in seminal plasma and seminal plasma Cd could affect semen quality
and induce oxidative DNA damage in human spermatozoa (Xu et al., 2003).
Based upon the data, it can be inferred that cadmium has the reproductive toxic
potential affecting semen quality.

Chromium and other
Chromium is naturally occurring compound present in rocks, soil,
plants, animals, volcanic dust etc. Trivalent chromium is an essential
element for living being. Chromium is generally used in metallurgy, chrome
plating, welding, chemical industry, wood preservation, photography and
as pigment etc. Occupational exposure to chromium generally occurs
through inhalation and dermal contact, although the general population
is exposed frequently by ingestion. Some reports appeared on semen
quality with respect to Cr exposure in humans in recent years. Danadevi et
al. (2003) reported deterioration in sperm quality among welders exposed
to nickel and chromium. They reported a significant positive correlation
between the percentages of tail defects and blood nickel concentration in
exposed workers and a negative correlation with sperm concentrations
and blood Cr levels. Further, a significant reduction in the sperm count,
motility and Zn levels whereas serum FSH level was significantly higher
among Cr exposed workers than the control (Li et al., 2001). Later Kumar
et al. (2005) reported that exposure to Cr has some effect on human sperm
as a significant positive association was observed between percentages of
abnormal sperm morphology and blood Cr levels. Further, CrVI disrupts
spermatogenesis by inducing free radical toxicity in non-human primate-
Macacaradiata Geoffroy, and supplementation of antioxidant vitamins
may be favourable to the affected subjects (Aruldhas et al., 2005).

Earlier Kumar (2004) reported that lead, cadmium and mercury
may have reproductive toxic potential to male reproductive health.
In addition, Meeker et al. (2008) reported the evidence for an inverse
association between molybdenum (Mo) and semen quality in human
and found the relationships are consistent with available animal data, but
additional clinical studies are needed. The data available suggests toxic
potential of some of the metals on male reproduction and metals may
directly affect the testicular tissues and affect hormonal production and
release or both or accumulate in reproductive organs causing long term
deleterious effects to the cellular and subcellular levels. Earlier, Danielsson
et al. (1984) reported based upon auto-radiographic studies in rodents
that Cd and Cr gathered in the interstitial tissues, demonstrating an
effect on hormone production, blood supply or both. Chowdhury (2009)
mentioned that metals could obstruct the gametogenic cells or Leydig cell
or spermatozoa directly. These effects may result in reduced fertility or
associated pregnancy waste, congenital malformation related with genetic
diseases. Moreover, the features of heat stress protein, Androgen-Binding
Protein, Cadherin and various stressor proteins alongwith reactive oxygen
species and neuro-endocrine mechanism are greatly affected by some of
heavy metals. Recently Sharma et al. (2014) found significantly higher concentration of chromium, cadmium and lead in hypospadias subjects,
which indicated association between high levels of cadmium, chromium,
and lead and risk of hypospadias.

Some other metals are also having reproductive toxic potential, but
epidemiological studies are inadequate and inconsistent. Bolt et al. (2012)
reported that reproductive toxicity of boric acid and borates is an issue
of concern. Based on experimental studies in rats, no-observed-adverseeffect
levels (NOAEL) dose were found to be 17.5 for male fertility and
9.6 mg Boron/kg b.wt. for developmental toxicity. Recently, occupational
studies in exposed cohorts were reported from Turkey and China which
showed negative results on male reproduction. Exogenous environmental
or workplace boron exposures were related with declines in Y- versus
X-bearing sperm. This can be undestood with the changes in offspring sex
ratios among men exposed to boron (Robbins et al., 2008). Later, Scialli
et al. (2010) reported non-significant differences in semen characteristics,
except sperm Y: X ratio in boron exposed workers. They concluded that
while boron has been shown to adversely affect male reproductive system
in laboratory animals, there is no obvious evidence of male reproductive
effects of boron to exposed workers.

Aluminium is one of the ubiquitous metals and used in industries,
pharmaceuticals, food additives and consumer products. Higher
concentration of aluminium in spermatozoa was associated with
decreased sperm motility (Hovatta et al. 1998). Recently Klein et al. (2014)
reported that the patients with oligozoospermia had a statistically higher
aluminum semen concentration and further analysis showed the presence
of aluminum in spermatozoa. Recently Berihu (2015) reported increase
oxidative stress, alteration in spermatogenesis as well as membrane
function, disruption in cell signaling and the impairment of blood testis
barrier, disturb the endocrine system which might be another possible
mechanism of Al induced male reproductive toxicity. Earlier, Pandey
and Jain (2013) provided a comprehensive account of the aluminium
induced male reproductive toxicity data on animal models. They reported
that increased oxidative stress, alteration in spermatogenesis as well as
in steroidogenesis, disruption in cell signalling, alterations in membrane
function and the diminishing of blood testis barrier, disturbance in
the endocrine system might be the several likely mechanisms of Al
induced male reproductive toxicity. Earlier Bedwal and Bahuguna (1994)
reported that Zinc content is high in the testis, and the prostate has a
highest concentration than other organs. Zinc deficit affects angiotensin
converting enzyme activity, and this leads to depletion of testosterone
and inhibition of spermatogenesis. Very recently, Roychoudhury et al.
(2016) summarized the existing knowledge on the effects of copper (Cu)
on the reproductive system. Short term administration of Cu was found
to exert harmful effect on intracellular organelles of rat ovarian cells.
Adverse effect of Cu on male reproductive functions has been indicated
by the decline in sperm concentration, viability and motility. Copper
nanoparticles can cause oxidative stress in vitro so leading to reproductive
toxicity. Recently Tvrda et al. (2015) mentioned that iron and copper
are essential trace nutrients playing significant roles in general health
and fertility. However, both are highly toxic when accumulating in huge
quantities and their impact on the structure and function of male gonads
and gametes is not known fully. Excess or deficiency of either may lead to
defective spermatogenesis, reduced libido, and induce oxidative damage
to the testicular tissue and spermatozoa.

Arsenic
Arsenic has chemical and physical properties intermediate between
a metal and a non-metal and is frequently mentioned to as a metalloid or semi-metal (IARC, 2012). Arsenic is a common environmental
pollutant derived from both natural and anthropogenic sources and
is extensively circulated all over the environment in the water, air and
land. People are exposed to higher levels of inorganic arsenic through
drinking contaminated water in various parts of world including eastern
part of India. Shen et al. (2013) investigated that environmental arsenic
exposure can impair male fertility. They showed that elevated urinary
concentrations of inorganic arsenic (AsiV) from general arsenic exposure
are significantly associated with male infertility, and arsenic species may
put forth toxicity via oxidative stress and sexual hormone disrupting
mechanisms, as showed by related biomarkers. Earlier, Xu et al. (2012) also
reported that reduced parameters in human semen quality are positively
associated with as exposure in a reproductive-age Chinese cohort.

Recently Sengupta et al. (2013) carried out a survey of geogenic
groundwater contamination with the heavy metals arsenic and cadmium
in Assam, India and found an increase in the incidence of male infertility
in this area. They enrolled patients with sperm concentration < 20x106/ml
were cases (oligozoospermic and azoospermic) and subjects with > 20x106/
ml (normozoospermic) and having fathered a child as control. They found
an inverse relationship between total sperm count and heavy metal in
drinking water as well as seminal plasma. The study also found significant
differences in the sperm function parameters like acrosome reaction,
hypo-osmotic swelling and nuclear chromatin de-condensation in the
patient group. Recently, Kim and Kim (2015) also reported that exposure
to inorganic arsenic induces alterations of spermatogenesis, reductions of
testosterone and gonadotrophins, and interruptions of steroidogenesis.
However, the mechanism of the reproductive and developmental problems
following arsenic exposure is poorly understood and need more studies.

Solvent
It is known that some of the solvents especially organic solvents are
having toxic potential to human health including reproductive system
of both sexes. Human can get exposed to solvents from various sources
mainly through inhalation, dermal and sometime less likely through
ingestion. They have been alleged to exert harmful effects on human
reproduction and associated function. Cherry et al. (2001) reported
a significant relationship between intensity of exposure to solvents
and clinical findings of < 12×106/ml motile sperm. Odds ratios, after
controlling for confounding factors, were 2.07 for moderate exposure to
solvents and 3.83 for high exposure. In the second series, the effect was
confirmed at high exposure to solvents but not at moderate exposure.
A statistically significant decline in sperm concentration was observed
during styrene exposure from 63.5 to 46.0 million sperm/ml. The total
sperm count was almost halved from an initial sperm value/ejaculate
(Kolstad et al., 1999). Later Migliore et al. (2002) examined sperm DNA
integrity in individuals occupationally exposed to styrene and found a
significantly higher DNA damage in sperm between subjects exposed to
styrene and the reference group.

Several reports are available with respect to exposure to benzene
and associated male reproductive health impairments. Marchetti et al.
(2012) reported that occupational exposures to benzene were linked
with increased incidence of chromosomally defective sperm, which
raise concerns for workers’ infertility, spontaneous abortions, mental
retardation and inherited defects in children. They also pointed out
benzene as a possible risk factor for de novo 1p36 deletion syndrome.
Because chromosomal aberrations in sperm can arise from faulty stem
cells/spermatogonia and promote concerns that occupational exposure
to benzene may have persistent reproductive effects in earlier exposed workers. Later Xing et al. (2010) reported that the work-related exposures
to benzene nearby 1 ppm induce aneuploidy in sperm. Sperm aneuploidy
elevated across low- and high-exposed groups for disomy X, and for
overall hyperhaploidy for the three chromosomes investigated. They also
found raised disomy X and hyperhaploidy in the nine men exposed to ≤ 1
ppm benzene. Song et al. (2005) assessed the effect of benzene on sperm
DNA of workers and found that higher concentration of benzene could
damage sperm DNA. Earlier Liu et al. (2003) also showed that benzene
exposure at higher concentration (42.29 mg/m3) may induce elevation
in occurrences not only of numerical aberrations for chromosome 1
and 18, but also induce structural aberrations in sperm chromosome 1
in exposed workers. Further, Katukam et al. (2012) reported a duration
dependent decrement in total sperm count and the percentage of motility
and increment of abnormal sperm morphology among the benzeneexposed
industrial workers. A significant increase in comet tail length was
also observed. Earlier, Xiao et al. (2001) also found a negative correlation
between sperm vitality, sperm activity, acrosin activity, or LDH-C4 relative
activity with working history of benzene, toluene, and xylene. These data
suggest that the mixture of these solvents could affect the sperm quality.
Later Barreto et al. (2009) reported that bioactivation of benzene can lead
to the development of harmful metabolites such as phenol, hydroquinone,
and catechol. Catechol forms semiquinones and reactive quinones that
might play a significant role in the generation of reactive oxygen species.
ROS can induce single and double strand breaks in the DNA, oxidized
nucleotides, and hyper-recombination, and consequently induces
deleterious genetic changes.

Toluene is a widely used industrial solvent, and humans may also
exposed to toluene through inhalation. Roeleveld (2006) assessed the risks
of reproductive disorders and birth defects in offspring of male painters
exposed to organic solvents. They found a positive relationship between
paternal occupational exposure to organic solvents and congenital
malformations. Nakai et al. (2003) investigated the effects of toluene on
the male reproductive system and injected toluene subcutaneously to male
rat for 10 days and found a decrease in the epididymal sperm counts and
the serum testosterone. Whereas 8-oxo-7,8-dihydro-2’-deoxyguanosine
formation in testes was increased. These suggest that toluene induces
reproductive toxicity via direct oxidative damage of spermatozoa.

Earlier Chia et al. (1996) examined the effects of trichloroacetic
acid (TCA) on spermatogenesis among workers exposed to TCA in an
electronics factory. Prevalence rate ratios of hyperzoospermia were
higher with respect to elevation of urine TCA levels compared to the “low
exposure” group, suggesting a dose-response relationship. Ratcliffe et al.
(1987) examined the semen quality of workers of the papaya fumigation
industry exposed to ethylene dibromide (EDB) and found statistically
significant decrease in sperm count per ejaculate, the percentage of viable
and motile sperm, and elevated morphological abnormalities (tapered
heads, absent heads, and abnormal tails). Earlier, Eskenazi et al. (1991)
investigated the effects of perchloroethylene (PCE) exposure dry cleaners
and laundry workers and reported that occupational exposures to PCE can
have subtle effects on sperm quality. Earlier, Welch et al. (1988) examined
the semen quality of painters who work in a large shipyard. The industrial
hygiene survey revealed that the painters were exposed to 2-ethoxyethanol
(2-EE) and to 2-methoxyethanol (2-ME). They found that painters had an
increased prevalence of oligospermia and azoospermia and an increased
odds ratio for a lower sperm count per ejaculate. Eldesouki et al. (2013)
studied painting workers exposed directly or indirectly to a mixture of
toluene, styrene and benzene at the work place and reported that the
testosterone was found to be significantly lowered, while, FSH and LH, were found to be significantly elevated in the exposed group. Exposure
to different concentrations of mixture of organic solvents (VOC’S)
had harmful effects on male reproductive hormones through a direct
testicular damage, especially in the long-term exposure workers. De
Celis et al. (2000) found that hydrocarbon exposure was associated with
an increased rate of semen abnormalities of exposed workers. The data
suggests that solvents especially organic solvents have adverse effects on
human reproduction and may also be associated with adverse pregnancy
outcome.

Radiation
The reproductive hazards and associated function due to ionizing
radiation have been well established, whereas reproductive hazards
associated from non-ionizing radiations are under intensive study.
The schedule of the delivered irradiation (total dose, chronic or acute,
number of fractions, and duration) is an important determinant of the
radiobiological effect of radiation on the tissues involved and differs
from tissue to tissue among different organ system (Ogilvy-Stuart and
Shalet, 1993). The age of the exposed person is also an important factor
for radiation effect. It is known that radiation is toxic to the reproductive
system and particularly the foetus and young ones and radiation may
affect chromosome, which may lead to congenital abnormalities. Streffer
(1995) mentioned that the embryo and fetus are extremely radiosensitive.
During the pre-implantation period radiation exposure at doses of 0.2 Gy
and higher can cause death of the embryo. Based on experimental data
with mammals, it was presumed that a radiation dose of about 0.2 Gray
(Gy) doubles the malformation risk. He further reported that studies in
humans suggest that the human embryo is more radio resistant than the
embryos of mice and rats. The time course of the loss of sperm production
is based on the fact that the rapidly dividing differentiating spermatogonia
are much more sensitive against ionizing radiation (Meistrich, 2013).
He also mentioned that treatment of cancer either with chemo- or
radiotherapy causes decline in sperm counts often to azoo-spermic
levels. This may persist for several years or be permanent. Recovery from
oligoo azoospermia is variable and depends on rate of killing of stem
cells and alteration of the somatic environment that normally supports
differentiation of stem cells.

A study of semen quality of cleaners of the Chernobyl sites, Ukraine
showed the decline of ejaculate volume, and spermatozoa with higher
immovable and degenerated forms. Maximal changes have been observed
among men who were exposed to 10 rem and above (Cheburakov and
Cheburakova, 1993). Later Goncharov et al. (1998) studied hormonal and
semen parameters in men who cleaned the territory around the Chernobyl
nuclear reactor (called ‘liquidators’). They reported that short-term
radiation exposure did not cause long-lasting disorder of endocrine status
and spermatogenesis. However, the study was 7-9 years retrospective;
therefore, it is not possible to understand the immediate effects of the
radiation exposure on endocrine status and spermatogenesis. Further,
Fischbein et al. (1997) also studied liquidators at Chernobyl in Ukraine and
found a significant difference in certain ultra-morphological parameters
of the sperm head between clean-up workers and controls of similar age.
Earlier Clifton and Bremner (1983) suggested that, spermatogenesis in
man is approximately 3.1 times more sensitive to ionizing irradiation as
compared to the mouse. Ogilvy-Stuart and Sahlet (1993) reported that
straight irradiation to the testis at lower doses; distress the germinal
epithelium and doses larger than 0.35 Gy led to reversible aspermia. The
time taken for regaining increases with larger doses; however, aspermia
may be permanent after doses above 2 Gy. Further, at higher doses i.e. > 15 Gy, Leydig cell function will also be impaired and in addition to dose
of radiation, the testis susceptibility is also dependent upon the age and
the pubertal status.

The safety of human exposure to various electromagnetic field sources
has become a debatable issue because of public health matter. Some data
are also available on low frequency magnetic fields and reproductive
health. Recently Gye and Park (2012) reported that various in vivo and
in vitro studies showed that electromagnetic field (EMF) exposure can
alter cellular homeostasis, reproductive and endocrine function, and
fetal development in animal systems. EMF exposure may change the
reproductive parameters such as male germ cell death, reproductive
endocrine hormones, sperm motility, the estrous cycle, early embryonic
development, reproductive organ weights, and pregnancy success. Further,
the effect of exposure on reproductive function differs with respect to
frequency and wave, strength, and duration of EMF exposure. Vignera
et al. (2012) reviewed both clinical and experimental studies on effects of
the exposure to mobile phones radiofrequency electromagnetic radiation
(RF-EMR) on male reproduction. They reported that human spermatozoa
exposed to RF-EMR have decreased motility, increased morphometric
abnormalities and oxidative stress; furher men using mobile phones have
also decreased sperm concentration, motility (especially rapid progressive
motility), viability and normal morphology. These seem to be related to
the duration of mobile phone use. There are number of in vitro and in vivo
reports which indicated that radiofrequency electromagnetic radiation
(mobile phones radiation) affects semen quality especially motility
(Erogul et al., 2006; Agarwal et al., 2008; Fejes et al., 2005; Gorpinchenko
et al., 2014). Fejes et al. (2005) found that the duration of possession and
the daily transmission time linked negatively with the rapid progressive
motile sperm. The low and high transmitter time groups also differed with
respect to the proportion of rapid progressive motile sperm. Agarwal et
al. (2008) reported that use of cell phones declines the semen quality by diminishing the sperm count, motility, viability, and normal morphology.
The decline in sperm parameters was dependent on the period of
exposure to cell phones. Erogul et al. (2006) suggested that EMR emitted
by cellular phone affects human sperm motility and long-duration EMR
exposure may lead to structural or behavioral changes of the male germ
cell. Further, Gorpinchenko et al. (2014) also found an association
between mobile phone radiation exposure, DNA–fragmentation level and
decreased sperm motility.

De Iuliis et al. (2009) reported that mobile phone radiation induces
DNA damage in human spermatozoa and Reactive Oxygen Species
production in vitro. RF-EMR enhances mitochondrial reactive oxygen
species generation by human spermatozoa, declining the motility and
vitality while motivating DNA base adducts formation and eventually
DNA fragmentation. Agarwal et al. (2009) also mentioned that
radiofrequency electromagnetic waves may lead to oxidative stress in
human semen. They speculated that possessing the cell phone in a trouser
pocket in talk mode may adversely affect spermatozoa and impair male
fertility. At the cellular level, an elevation in free radicals and [Ca2+] i
may facilitate the effect of EMFs and causes cell growth inhibition, protein
misfolding, and DNA breaks. The effect of EMF exposure on reproductive
function depended upon frequency and wave, strength, and duration
of exposure (Gye and Park (2012). Falzone et al. (2011) concluded that
although RF-EMF exposure did not negatively affect the acrosome
reaction, it had a noteworthy effect on sperm morphometry. A significant
decline in sperm binding to the hemizona was observed. This shows a
noteworthy effect of RF-EMF on sperm fertilization potential. However, a
study from Denmark reported that exposure to extremely low frequency magnetic fields is not deleterious to fertility (Hjollund et al., 1999). Most
of the available data suggest that exposure to ionizing and non-ionizing
radiation particularly EMF may have significant adverse effect on human
sperm which are associated with fertility reduction.

Exposure to plasticizers
Plasticizers are substances which generally added to a material usually
the PVC to boost its flexibility and elasticity. They are widely used in many
commercial applications. The general population is exposed to these
chemicals through consumer products as well as through diet and medical
treatments. A concern exists over whether additives in plastics, such as
phthalates, bisphenol A or polybrominated biphenyl ethers, may affect
human health by changing endocrine function or through other biological
mechanisms. Several clinical and experimental studies were published
on exposure to phthalates and reproductive health. Duty et al. (2003a)
determined the effect of environmental levels of phthalates on DNA
integrity in human sperm. They reported that elevation in specific gravityadjusted
monoethyl phthalate (MEP) level, the comet extent increased
significantly; the tail distributed moment also increased. Monobutyl,
monomethyl, monobenzyl, and mono-2-ethylhexyl phthalates were
not associated with comet assay parameters. This demonstrated that at
environmental levels of urinary MEP, is related with the increased DNA
damage in human sperm. Later, Zhang et al. (2006) monitored the
phthalates such as di-ethyl phthalate; di-n-butyl phthalate; di-2-ethylhexyl
phthalate were detected in semen of most of the samples. A significant
positive association was noticed between liquefied time of semen and
phthalate concentrations. However, no significant difference was found
between phthalate concentrations and sperm density or livability.
Although the level of phthalates is relatively mild, but an association of
phthalate levels and reduced semen quality was noticed. Further, Wang et
al. (2015) found the urinary concentrations of monobutyl phthalate were
positively associated with the below-reference sperm concentration and
sperm count. They also observed significant dose-dependent relationships
of the urinary mono-(2-ethylhexyl) phthalate (MEHP) and the percentage
of di-(2-ethylhexyl)-phthalate metabolites (DEHP) excreted as MEHP with an increased percentage of abnormal sperm heads. Duty et al. (2003b)
explored the association whether environmental levels of phthalates are
related with altered semen quality in humans. They reported that there
were dose-response relations for monobenzyl phthalate and monobutyl
phthalate with one or more semen parameters, and suggestive
confirmation for monomethyl phthalate with sperm morphology. The
lack of a relationship for other phthalates may indicate a difference in
spermato-toxic potential among phthalates. Later, Pant et al. (2008) found
that urban population have significantly higher levels of phthalate esters
than the rural. Further, infertile men showed significantly higher levels
of pollutants in the semen than fertile men. A negative relationship was
found between semen level of DEHP and sperm quality and positive link
with depolarized mitochondria, elevation in LPO and ROS production,
DNA fragmentation. These findings suggest that phthalates might be
one of the causative factors associated with the deterioration in semen
quality and adverse effects of phthalate might be through mitochondrial
dysfunction, ROS, and LPO mediated. Swan (2008) did a literature survey,
on human health endpoints following prenatal, neonatal, childhood, as
well as adult exposures to phthalates. At least one significant link has
been stated for urinary metabolites of butylbenzyl phthalate, diethyl
phthlate, di-n-butyl phthalate, and di-isononyl phthalate and for three
of the urinary metabolites of di(2-ethylhexyl) phthalate. Many of the
findings reported, have been found in males are consistent with the antiandrogenic
action. Earlier, Murature et al. (1987) mentioned the existence of significant negative correlations between mean sperm densities and
production of synthetic organic chemicals. Phthalate esters are one class
of organic chemicals that are identified to disrupt testicular function in
laboratory animals.

Swan et al. (2005) provide information on Ano-genital distance (AGD)
and other genital assessments with respect to prenatal phthalate exposure
in humans. AGD was significantly interconnected with penile volume and
the section of boys with incomplete testicular descent. They calculated the
ano-genital index (AGI) as AGD divided by weight and found that urinary
concentrations of four phthalate metabolites (monoethyl, monobenzyl,
mono-n-butyl, and monoisobutyl phthalate) were inversely associated to
AGI. The associations between male genital development and phthalate
exposure are steady with the phthalate-associated syndrome of incomplete
virilization that has been described in prenatally exposed rodents. The
data obtained support the assumption that prenatal exposure to phthalate
at environmental levels can unfavourably affect male reproductive
development. Later, Desdoits-Lethimonier et al. (2012) investigated the
effects of mono-(2-ethylhexyl) phthalate (MEHP) and di-(2-ethylhexyl)
phthalate (DEHP) on organo-cultured adult human testis and a human
cell line. In both models, DEHP and MEHP significantly repressed
testosterone production and provide evidence that DEHP and MEHP
can prevent testosterone production in the adult testis. They mentioned
that this observation is consistent with recent epidemiological findings
of an inverse relationship between exposure to MEHP and testosterone
concentrations. However, Jönsson et al. (2005) mentioned no clear
pattern of links were observed between mono butyl phthalate (MBP),
mono benzyl phthalate (MBzP), and mono ethylhexyl phthaltale (MEHP)
with any of the reproductive biomarkers. Subjects within the highest
quartile for mono ethyl phthalate had fewer motile sperm, more immotile
sperms, and lower LH values, but there was no harmful effect for most
other endpoints. They found weak links between one phthalate biomarker
and impairment of reproductive function biomarkers. Duty et al. (2005)
assessed an association between environmental levels of phthalates and reproductive hormones in men. An interquartile range (IQR) change in
MBzP exposure was associated with a 10% decline in FSH level. Further,
an IQR change in monobutyl phthalate (MBP) exposure was linked with
a 4.8% elevation in inhibin B. An association was found between urinary
concentrations of MBP and MBzP and altered levels of inhibin B and
FSH, but, the hormone concentrations did not change in the anticipated
patterns.

Liu et al. (2012) investigated the exposure of a Chinese reproductive
age cohort to ubiquitous phthalates pollutants and semen quality. They
observed a borderline-significant dose–response relationship between
MBP and sperm concentration. But not significant relationship with
MMP and MEP, a significant positive correlation between MEP and
straight-line velocity of sperm motion was observed. Ealier, Meeker et al.
(2009) reported that the ratio of testosterone to estradiol was positively
associated with MEHP, suggesting prospective relationships with
aromatase suppression. These results suggest that urinary metabolites
of DEHP are inversely related with circulating steroid hormone levels.
Huang et al. (2011) investigated possible associations between semen
quality and di(2-ethylhexyl) phthalate (DEHP) in personal air of workers
of polyvinyl chloride plants. The workers were divided into low- and high-
DEHP-exposed groups with respect to the levels of DEHP in personal
air. DEHP showed positive associations with sperm DNA denaturation
induction and DNA fragmentation index and negative associations with
sperm motility.

Fredricsson et al. (1993) studied the effect of various phthalates and
extracts from diesel particulate material on human spermatozoa in vitro.
All these compounds inhibited sperm motility in a dose-response manner.
Sperm motility was more affected by diethylhexyl and dibutyl phthalates.
Significant effects were noted for phthalates with regard both to motility
and to some form of the qualities of motility, such as velocity, linearity
and amplitude of the track. Regarding the effects on sperm motion, di-noctyl
phthalate appeared to be the least toxic, trailed by dibutyl phthalate.
The initial effects of diesel particulate extracts were moderate with respect
to percent motile sperm but higher exposure the effects became more
pronounced. Later Lottrup et al. (2006) reported that phthalates adversely
affect the male reproductive system in animals, inducing hypospadias,
and cryptorchidism, reduced testosterone production and declined
sperm counts. Exposre to phthalate effects are much more severe after in
utero than adult exposure. They also mentioned that human testicular
development might be susceptible to phthalates. Five of six phthalates
[monoethyl-(MEP), monobutyl- (MBP), mono-2-ethylhexyl- (MEHP),
monomethyl- (MMP), and mono-isononyl phthalate (MiNP)] revealed
relationship with hormone levels in healthy boys, which were indicative of
poorer androgen activity and reduced Leydig cell function. MEP and MBP
were positively related with serum sex hormone-binding globulin levels.
MMP, MEP, MEHP MBP, MBP, and MiNP were also positively related
with the LH/testosterone ratio. A reduction of the anogenital index (AGI)
in infant boys with rising concentrations of MBP, MEP, monobenzyland
mono-isobutyl phthalate in maternal urine during late-pregnancy
was also reported. Boys with lower AGI showed a high occurrence of
cryptorchidism and small genital size. Recently Oceane and Bernard
(2014) highlights the fact that i) there is a vast gap between the number
of studies executed in animals and humans, ii) there are differences in
the mode of rats, mice, primates and humans to respond to phthalates
iii) additional work is necessary to clarify the contradictions, in the few
prevailing human epidemiological studies, which may be partly explained
by different methods of exposure assessment iv) in accordance with
latest findings in rodents, it cannot be excluded that transgenerational effects of phthalates and/or epigenetic alterations exist in humans v)
methodological restrictions need to be solved for the xenografting and
in vitro models using human fetal testis to fulfil ‘missing link’ amongst
epidemiological studies and rodent models and vi) epidemiological and
in vitro studies generally converge adequately to determine that phthalate
anti-androgenicity is plausible in adult men. Recently Yuan et al. (2017)
also reported that DBP exposure during pregnancy (8 to 14 days)
significantly decreased the sperm counts in F1 through F3 generation.
They found distinct metabolic changes in the testis of both F1 and F3
generation offspring.

Pesticides/Insecticides
The World Health Organization (2001) reported that there are about 3
million cases of pesticide poisoning every year and up to 220,000 deaths
occurs, mostly in developing countries. The application of pesticides
is often not very specific, and sometime unintended exposures occur
without the knowledge of exposed persons. Pesticides also have the
potential to damage the nervous system, endocrine system and the
reproductive system. Pesticides can even be harmful to foetuses because
the chemicals can pass from the mother to developing foetus in the womb
during pregnancy and affect the pregnancy and outcome. Pesticides can
enter the body during mixing, applying, or clean-up operations through
dermal, inhalation and ingestion. Apart from pesticide factory workers
and/or applicators, the general population is also exposed to these
pesticides or their metabolite to some extent, even through the food chain. It is rational to believe that pesticides, which are toxic to pest, might
produce some adverse health effect including reproductive effect on living
beings including humans. The United Nations Environment Protection
(UNEP) agency reported that nine of the twelve most unwanted persistent
organic pollutants (POPs) are pesticides used on agriculture crops and
for public health vector control programmes. These twelve POPs have
been acknowledged by the UNEP organization as a powerful threat to
human and wildlife health on a global basis (Fisher, 1999). Exposure to
pesticides could be one of the contributing cause to the falling semen
quality and growing trends of infertility. Adverse effects of pesticides
in the environment received extensive attention about half century ago.
It has been hypothesized that long term, low level of exposure of these
chemicals are more linked to human health effects such as endocrine
disruption, immuno-suppression, reproductive abnormalities and cancer
(Srinivasa et al.2005).

Exposure of human to pesticides may occur by their occupation,
environment or food chain. A classic example of reproductive toxicant
is 1, 2-dibromo-3-chloropropane (DBCP), spermatotoxic effects of
DBCP was reported in the 60s in rats but its harmful effects on human
spermatogenesis were revealed only in 1977. Paucity of children was
noted among the workers in a 1–2, Dibromo-3-chloropropane (DBCP)
manufacture plant, USA (Whorton et al., 1977). Further, they reported
the clear-cut difference in both the distribution of sperm counts and the
median counts between the exposed and the non-exposed men with DBCP.
Another study on DBCP exposed workers in a pesticide factory in Israel
reported complete atrophy of the seminiferous epithelium (Postashink
et al., 1978). This suggests that DBCP is a powerful male reproductive
toxicant. Later Mattison et al. (1990) studied the hormonal profile and
semen of male workers involved in the DBCP manufacture and reported
high level of LH and FSH in serum and a reduced sperm count. Recently,
Easley et al. (2015) examined the effects DBCP and 2-bromopropane
(2-BP) on in vitro human spermatogenesis. They reported that acute
exposure to 2-BP or DBCP induces a decline in germ cell viability by
apoptosis. DBCP and 2-BP affect viability of diverse cells as 2-BP mainly
reduces spermatocyte viability whereas DBCP exerts higher effect on
spermatogonia. Both 2-BP and DBCP induce reactive oxygen species
leading to an oxidized cellular environment. Based upon the data one can
conclude that DBCP is an effective male reproductive toxicant affecting
both reproductive and endocrine function.

In addition to DBCP, there are reports of reproductive toxicity of a
few other pesticides also. Carbaryl (1-naphthyl-N-methyl carbamate) is
a broad-spectrum insecticide used to protect fruits, vegetables, cereals,
cotton, and other crops against a variety of insects and pests. Wyrobek et
al. (1981) reported that the carbaryl induced a significantly higher amount
of sperm with abnormal head shapes among workers and confounders
like age, smoking habits, and medical problems did not appear to affect
the result. Later Meeker et al. (2004a) also found associations between
altered semen quality and 1-naphthol (1N), a metabolite of carbaryl
and naphthalene are consistent with previous studies of carbaryl
exposure. They also reported that environmental exposure to carbaryl
and chlorpyrifos may be associated with elevated level of DNA damage
in human sperm (Meeker et al., 2004b). Xia et al. (2004) also showed a
significant higher percentage of sperm abnormality and fragmented DNA
in carbaryl-exposed workers. Further, the frequencies of aneuploidy and
numerical chromosomal abbrations showed significant difference between
exposed and control groups. They suggested that carbaryl might induce
spermatozoa morphologic abnormalities as well as genotoxic defects
among exposed workers. The available studies indicate the toxic effects of carbaryl on testicular functions that are essential for reproductive success.

DDT is given credit to help ~1 billion people live free from malaria,
which in turn saved millions of lives. In 1973, after 30 years of worldwide
use of DDT, a WHO report concluded that the benefits derived from use
of this pesticide were far bigger than its possible hazards (WHO, 1973).
This suggests the benefits of DDT, however its stability, persistence in
the environment and ubiquitous presence, accumulation in adipose
tissues, and estrogenic properties raise concern about its possible longterm
adverse effect (Turusov et al., 2002). DDT might be beneficial in
controlling malaria, but the evidence of its harmfull effects on human
health necessities appropriate research on whether it attains a favourable
balance of risk versus benefit (Rogan and Chen, 2005). Aneck-Hahn et al.
(2007) reported that DDT has estrogenic potential, and its main metabolite,
p, p′-dichlorodiphenyl-dichloroethylene (p, p′-DDE), is a potent antiandrogen.
In a cross-sectional study, male subjects were enrolled from an
endemic malaria area where DDT is sprayed annually. The data indicated
that mean sperm motility was lower with a higher p, p′-DDE level and
a significant positive relationship was found among percent sperm with
cytoplasmic droplets and p, p′-DDT level. The ejaculate volume was
poorer than the normal range. Twenty-eight percent of the study subjects
presented with oligozoospermia, with a significant positive association
with p, p′-DDE. Further, a significant positive association was observed
with asthenozoospermia (32%) and p, p′-DDT and p, p′-DDE. The
results suggest that non-occupational exposure to DDT is associated with
impaired seminal quality. Later, Tavares et al. (2013) showed a novel nongenomic
mechanism specific to sperm. They reported that p, p’-DDE was
able to induce [Ca (2+)]i in human sperm through the opening of CatSper
subsequently conceding male fertility. The promiscuous nature of CatSper
stimulation may predispose human sperm to certain persistent endocrine
disruptors.

A few studies are also available on the effects of multiple pesticides
exposure on the reproductive system of male workers, which may also
affect the reproductive outcome. A study conducted by Rupa et al. (1991)
among male workers who were exposed to several pesticides such as
DDT, BHC, endosulfan; and organophosphorus pesticides i.e. malathion,
methyl-parathion, dimethiote, monocrotophos, phosphamidon and
quinalphos; synthetic pyrethroids such as fenvelrate and cypermethrin
during mixing and spraying of pesticides showed male mediated adverse
reproductive outcome such as abortion, stillbirths, neonatal deaths,
congenital defects, etc. However, it is not possible to identify any specific
pesticide based on these results as these are cumulative effects of several
pesticides. Later, Petrelli and Figà-Talamanca (2001) examined the
interference of pesticide exposure on male fertility by studying time to
pregnancy (TTP) among green house workers and found an elevation in
the risk of conception delay among the green house workers with high
pesticide exposure. Further, Frazier (2008) reported that exposure of men
or women to certain pesticides at adequate doses may elevate the risk for
sperm abnormalities, decreased fertility, and a deficit of male children,
spontaneous abortion, fetal growth retardation or birth defects.

Thakur et al. (2010) conducted a study to ascertain an association
between heavy metal, pesticide exposure and reproductive and child
health. Spontaneous abortion and premature births were considerably
higher in area affected by heavy metal and pesticide pollution. A larger
percentage of children were reported to have delayed milestones, language
delay, mottling of teeth, blue line in the gums, and gastrointestinal
morbidities. They concluded that although no direct association could be
established, but heavy metal and pesticide exposure may be potential risk factors for reproductive and child health outcomes. Earlier Petrelli et al.
(2000) conducted study among male pesticide applicators occupationally
exposed to pesticides and control (food retailers). The ratio of abortions/
pregnancies among wives of applicators was 0.27 and for retailers 0.07.
The Odd Ratio for spontaneous abortion adjusted for age of wife and
smoking of parents was 3.8 times greater than for the control population.
Queiroz and Waissmann (2006) provide a critical review on work-related
chemical substances capable of causing male infertility. They reported
that pesticides such as DDT, linuron, and some others, heavy metals like
mercury, cadmium, lead, copper and industrial substances and residues
such as polychlorinated biphenyls, dioxins, ethylene dibromide, polyvinyl
chloride, phthalates etc are among the main endocrine disruptors that can
affect male infertility. Gonadal dysfunction and congenital malformation
are the main alterations produced by these in the male reproductive
system. Recently, Mehrpour et al. (2014) reviewed the data on exposure
to pesticides and semen quality and fertility and reported that semen
quality changes are multifactorial in origion as there are numerous factors
affecting sperm quality in occupational exposures. Most of pesticides
including organophosphoruses may affect the male reproductive system
by reduction of motility and sperm density, inhibition of spermatogenesis,
reduction of testis weights, sperm counts, viability, motility, density, and
inducing sperm DNA damage, and increasing abnormal morphology.
Reduced weight of testes, epididymis, seminal vesicle, and ventral prostate,
seminiferous tubule degeneration, change in plasma levels of testosterone,
follicle-stimulating hormone, and luteinizing hormone, decreased level of
the antioxidant enzymes in testes, and inhibited testicular steroidogenesis
are other possible mechanisms of male reproductive health impairment.

Exposure to Heat
It is known that temperature influences the development of germ
cells as well as reproductive cycle of living beings. Temperature plays an
important role in the spermatogenesis of human beings. Therefore, nature
has kept the scrotum outside the human body so that the temperature
of the testis lowers than that of the body temperature. The first report of
working heat exposure was in 1775 when an English physician Percival
Pott recognized a high occurrence of scrotal cancer in chimney sweepers.
It is well known that in most of the living being including human
spermatogenesis is temperature dependent phenomenon. Mammalian
testes are located outside the body to keep temperature below the core
body temperature which is necessary for normal spermatogenesis.
Elevation in scrotal temperature can disrupt its progression leading to
poor sperm quality and infertility. Thonneau et al. (1998) reported that
several experimental studies showed that artificial increases in scrotum
or testicle temperature in fertile men lessen both sperm productivity and
quality. They concluded that occupational heat exposure is an important
risk factor for male infertility, affecting sperm morphology and followed
delayed conception. Sadighi et al. (2003) from Iran, pointed out that some
factors in the human environment, such as certain working conditions,
can put the human reproductive system at risk. This study showed that
34.1% affected by heat. Another study which was carried out among men
who reported problems with infertility attended at infertility clinic, Iran
also showed that out of 1164 subjects. 42.8% were exposed to heat during
the work (Vaziri et al., 2011).

It is known that work processes such as iron foundry, baking, ceramic
industry, welding etc generate high temperatures, which are unfavourable
to the functioning of the reproductive system. Earlier Bonde (1992)
investigated the semen quality and sex hormone levels among welders
with a moderate exposure to radiant heat, but without substantial exposure to welding fume toxicants and found that the welders experienced a
reversible decrease in semen quality, likely caused by a moderate exposure
to radiant heat. Later, Kumar et al. (2003) also reported that, welding
may have had some adverse effects on sperm motility, morphology and
physiologic function even though sperm concentration was in the normal
range. Earlier Figa-Talamanca et al. (1992) carried out a study among
ceramics oven operators with a longer exposure to high temperatures.
The data showed that exposed individuals had a higher incidence of
childlessness and struggle in conceiving. The semen analysis showed no
significant alterations except in sperm velocity. Although changes in semen
parameters, taken singly, were not statistically significant, hoewever, the
overall assessment of the sperm parameters indicated a higher occurrence
of pathologic sperm profiles among the exposed ceramics workers.

Jung and Schuppe (2007) reported that duration of sitting during work
positively associated with daytime scrotal temperatures and daytime
scrotal temperature negatively links with semen quality. They mentioned
that fertility parameters of professional drivers with long periods of sitting
in vehicles were impaired. Further, relationship between wearing tight
fitting underwear and higher scrotal temperatures was also observed.
The observations suggesting a link between tight-fitting underwear
and impaired semen quality are not convincing. They further reported
that scrotal and testicular cooling is capable to recover semen quality.
Earlier, Figà-Talamanca et al. (1996) explored the possible association
between the work exposures of professional drivers and reproductive
health; the data suggest that prolonged urban automobile driving might
be risk factors for sperm quality, and especially for sperm morphology.
Recently Garolla et al. (2015) reported a significant increase in 24-h
mean scrotal temperature in both obese and men with a varicocele. The
increase in scrotal temperature was associated with higher FSH plasma
levels and impaired sperm parameters as compared to controls. Hjollund
et al. (2002a) mentioned that measuring scrotal temperature offers a
valid assessment of testicular temperature. They mentioned that work
position is an important determinant of testicular temperature. They
also reported that both scrotal temperature and semen quality are closely
related. Sedentary work in ordinary jobs, although a strong determinant
of scrotal temperature, does not seem to affect semen quality (Hjollund
et al., 2002b). Later Stoy et al. (2004) conducted a study to understand
the possible deleterious effects of sedentary work on semen characteristics
and found that sedentary work is a risk factor for impairment of semen
characteristics.

Nowadays laptop computers (LC) have become part of a modern
lifestyle and have gained popularity among the younger reproductive
age population all over the world. Sheynkin et al., (2005) evaluated the
thermal effect of LC on the scrotum. Working on LC in a laptop position
causes significant Scortal Temperature elevation because of heat exposure.
Long-term exposure to LC-related scrotal hyperthermia may have a
negative impact upon spermatogenesis. Further, studies of such thermal
effects on male reproductive health are needed. Based on these data one
can suggest that exposure to high temperatures has an adverse effect on
male reproductive system and it is one of the important risk factors for
male infertility.

Environmental Exposure and Reproductive Health
All the living being including human beings are exposed to several
toxicants, physical factor such as natural radiation, ultraviolet radiation,
heat etc. during their day-to-day activities without the knowledge of
exposed individuals. Some of them may affect their reproductive health
and outcome.

Air pollutants
There is a growing epidemiologic literature reporting association
between air pollutants and reproductive outcomes in recent decades.
The air pollutants are both man made as well as natural. The major
air pollutants are toxic gases and metals, particulate matter, etc.
in the environment. Jurewicz et al. (2009) evaluated the impact of
environ¬mental toxicants exposures such as pesticides, phthalates, air
pollutants, PCBs, trihalomethanes (THMs), mobile phones on semen
quality and suggested that there are strong signs that some pesticides
besides DBCP (DDT/ Dichlorodiphenyldichloroethylene), eth¬ylene dibromide,
organophosphates) affects sperm count. PCBs are detrimental
to sperm motility while air pollution, data advocate a link between
ambient air pollutants and semen characteristics. Several recent studies
showed that exposure to environmental air pollutants affect reproductive
functions especially, produced adverse effects on pregnancy outcomes,
fertility, and fetal health. Epidemiological studies demonstrated that
exposure to ambient levels of air pollutants related to intrauterine growth
retardation, low birth weight, prematurity, neonatal death, and reduced
fertility in males (Veras et al., 2010).

Recently Rzymski et al. (2015) reported that environmental
deterioration can lead to the higher risk of exposure to heavy metals, and
subsequently, health implications including impairments in reproduction.
Thus, it is therefore important to continue the studies on metal-induced
mechanisms of fertility impairment on the genetic, epigenetic and
biochemical level. Very recently Skakkebaek et al. (2016) mentioned that
environmental exposures arising from modern lifestyle, then genetics,
are the most important factors in the observed deteriorating trends of
male reproductive health. These might act either directly or via epigenetic
mechanisms. In the later case, the effects might have an impact upon
their offsprings after exposure. The potential effect of POP related air
pollution on male reproductive system has attracted scientific community,
policymakers and the public in recent decade. Therefore, epidemiological
studies should examine the impact of chronic exposure of POPs via
inhalation on fertility (Hsu et al., 2014). Later Radwan et al. (2016) provides
suggestive evidence of a relationship between ambient air pollution
and sperm quality. Recently Wu et al. (2017) quantitatively assessed the
association between particulate matter PM exposure and semen quality
and reported that ambient PM exposure during sperm development,
adversely affects semen quality, especially sperm concentration and
count. Later Zhou et al. (2018) investigated the associations between air
pollutants PM10, PM10-2.5, and PM2.5 exposures and semen quality,
sperm DNA fragmentation and reproductive hormones. They found the
evidence that air PM10 and PM10-2.5 exposures, not PM2.5, are the risk
factors of semen quality. Very recently Nobles et al. (2018) reported that
ambient air pollution is associated with increases in oxidative stress, to
which sperm are particularly sensitive. They concluded that air pollution
exposure was not associated with semen quality, except for sperm
head parameters. Moderate ambient air pollution may not be a major
contributor to semen quality. Further research is needed to explore this
association. Individual precise exposure assessment would be needed for
more detailed risk characterization with respect to air pollutants.

Endocrine Disruptors
There is mounting evidence that exposure to some of the pesticides/
metals/plasticizers disrupts the endocrine system, creating disorder with
the complex regulation of hormones, the reproductive system, embryonic
development and pregnancy outcome. Endocrine disruption can create
infertility, a diverse birth and developmental defects in offspring, including hormonal imbalance and incomplete sexual development,
impaired brain development, behavioural disorders, etc. A wide range
of substances in addition to some of the pesticides, both natural and
man-made substances, reported to cause endocrine disruption, which
includes some pharmaceuticals, polychlorinated biphenyls, dioxin
and dioxin-like compounds, DDT and some other pesticides, and
plasticizers such as bisphenol A and few phthalates and phytoestrogens
etc. Birnbaum (1994) reported that some of the environmental chemicals
may be associated with endocrine modifications in people, wildlife,
and experimental animals. Persistent environmental chemicals such as
dioxins and PCBs have been shown to modify the activities of several
different hormones. He also mentioned that the unborn child or the
neonate may be at danger from these chemicals because of their rapid
growth and development. Safe (2000) hypothesized that environmental
exposure to synthetic estrogenic chemicals and related endocrine-active
compounds may be responsible for a global decline in sperm counts,
diminished male reproductive capacity, and breast cancer in women. The
data on organochlorine contaminants (DDE/PCB) levels indicated no
significant difference between breast cancer patients and control. Thus,
many of the male and female reproductive tract problems associated with
endocrine-disruptive hypothesis have not elevated and are not associated
with these contaminants. However, they mentioned that this does not
exclude an endocrine-etiology for adverse environmental effects or
human problems associated with exposures to such chemicals. Murray et
al. (2001) mentioned that there is now considerable evidence that male
reproductive function is declining. Some chemicals have shown to disturb
the developing fetal endocrine system in laboratory animals treated
in utero. Studies on animal in vivo and human in vitro have identified
EDC sensitive genes. Therefore, hypotheses are being postulated with
respect to the mechanism of action e.g. disturbed testicular apoptosis and
altered hepatic biotransformation of steroids. They reported that several
confounding factors include: a) the huge number of chemicals termed
EDCs, b) the capability of chemicals to bioaccumulate in body lipid, c) the
metabolism of body lipid during pregnancy releasing the EDC legacy into
circulation and (d) the poorly understood kinetics of EDC transfer across the placenta. Despite substantial effort to understand the mechanisms by
which these endocrine disrupting chemicals exert their effects are still
mostly unknown.

Earlier Kavlock et al. (1996) put forward a hypothesis that humans and
wildlife species suffered adverse health effects after exposure to endocrinedisrupting
chemicals. These adverse effects include declines in wildlife
populations, upsurges in cancers, and reduced reproductive function.
Sikka and Wang (2008) reported that endocrine disruptors are estrogenlike
and anti-androgenic chemicals in the environment. They mimic
natural hormones, inhibit the action of natural hormones, or modify
the normal function of the endocrine system and have potential harmful
effects on male reproductive axis causing infertility. Although testicular
and prostate cancers, undescended testis, chronic inflammation, Sertolicell-
only pattern, abnormal sexual development, hypospadias, altered
pituitary and thyroid gland functions are also observed, the available
data are insufficient to assume worldwide conclusions. They also reported
that newer tools for the recognition of Y-chromosome deletions further
strengthened the assumption that the decline in male reproductive health
and fertility might be related to the presence of certain toxic chemicals in
the environment. Maffini et al. (2006) also reported that the quantity and
quality of human sperm has declined and the incidence of male genital
tract defects, prostate, testicular, and breast cancer has elevated during
the last 60 years. During the same time, developmental, reproductive and endocrine effects have also been recognized in wildlife species. They
mentioned that perinatal exposure to environmentally relevant BPA doses
results in functional and morphological changes of the female and male
genital tract and mammary glands that may predispose the tissue to prior
commencement of disease, reduced fertility and prostate and mammary
cancer.

Mendiola et al. (2010) observed no significant associations between
semen parameters and urinary BPA concentration. However, a significant
reverse association was found between urinary BPA concentration and
free androgen index (FAI) levels and the FAI/LH ratio, and a significant
positive association were also found between BPA and SHBG. They
suggested that, in fertile men, exposure to low environmental levels
of BPA may be associated with a modest decrease in markers of free
testosterone, but effects on reproductive function are expected to be
small. Further, Bustamante et al. (2010) concluded that the levels of the
metabolites pp’DDT and β-HCH are higher among mothers of newborns
with cryptorchidism. They mentioned that exposure to substances
during fetal development with anti-androgenic effects could produce
endocrine disruption, such as cryptorchidism. Earlier Waliszewski et al.
(2005) also noted that the levels of the metabolites pp’DDT and β-HCH
are higher among mothers of newborns with cryptorchidism. It is
possible that substances with anti-androgenic effects could produce such
effect. Rignell-Hydbom et al. (2005) conducted a study among Swedish
fishermen who were consuming low and high fatty fish, an exposure
source of persistent organochlorine pollutants (POPs) and found that
exposure to POP may have a minor negative impact on sperm chromatin
integrity. Knez (2013) mentioned that Bisphenol A, phthalates and
alkylphenols are essential components of multiple products, thus they
are ubiquitously present in the environment. They can exert detrimental
effects on the male reproductive system under laboratory conditions.
However, human exposure data are scanty and do not support toxicity
data of these substances at environmental concentrations level. Recently Jeng (2014) reported that the male reproductive system may be vulnerable
to the effects of endocrine disrupting chemicals. He emphasized the need
for 1) well-defined longitudinal epidemiology studies, with properly
designed exposure assessment to understand exposure and effect causal
relationships; 2) chemical and biochemical approaches intended to
understand the mechanism of action of xenoestrogens with respect to
low-dose effects, and to identify genetic susceptibility factors associated
with the risk of harmful effects of EDCs.

The data available suggests that the chemical having endocrine
distrupting potential may have adverse effect on male reproduction and
associated reproductive function by affecting the endocrine system and
these chemicals act at an environmentally relevant very low doses.

Life style and reproduction
It is establishing that lifestyles associated diseases are increasing worldwide
including India during the last few decades because of changes in
lifestyle pattern. There have been progressive changes in many aspects of
our diet, lifestyle as well as environment during the last half century. Poor
lifestyle adopted by the human such as tobacco smoking and chewing,
excess use of alcohol, use of illicit drugs, unhealthy diet, lack of physical
activity, excess use of electric gadgets etc may lead to several diseases
which are yet preventable by switching over to healthy life style. It is also
getting to establish the fact that some of these life styles factor might also
be behind the cause of deterioration of reproductive health observed in
recent decades. Tobacco chewing and smoking have adverse effects on
oral cavity or lung cancer predominantly. However, there are reports that tobacco smoking also affects reproduction. This may also be true for
tobacco chewing.

Tobacco smoking and chewing
Mostafa (2010) pointed out that most of the reports showed that
smoking reduces sperm production, normal forms, motility and fertilising
capacity through increased DNA damage and seminal oxidative stress.
He concluded that although some smokers may not experience reduced
fertility, men with marginal semen quality can benefit from quitting
smoking. Recently Lotti et al. (2015) suggested that smoking may negatively
affect seminal vesicles, volume in an independent manner, as the difference
between current smokers and non-smokers retained significance after
adjusting confounders. Earlier Homan et al. (2007) mentioned that
there is strong evidence that age, weight and tobacco smoking have
adverse impact on general as well as reproductive health. Al-Matubsi
et al. (2011) also reported that smokers had significantly lower sperm
concentration and motility and higher serum testosterone and luteinizing
hormone levels than non-smokers. Calogero et al. (2009) studied the
effects of cigarettes smoke extract (CSE) on motility, chromatin integrity,
mitochondrial membrane potential (MMP), and apoptosis in spermatozoa
in vitro of non-smokers. CSE suppressed sperm motility and elevate the
number of spermatozoa with low MMP, the leading source of energy
for motility. In addition, CSE had a harmful effect on sperm chromatin
condensation and apoptosis. It increased the number of spermatozoa with
phosphatidylserine externalization and fragmented DNA, in a dose and
duration dependent manner. Yu et al. (2014) investigated the relationship
between smoking, the histone-to-protamine transition ratio in sperm and
semen quality. Smoking is strongly linked with deformities in histone-toprotamine
transition and with alteration of protamine mRNA expression
in human sperm. The percentage of sperm DNA fragmentation index,
sperm with abnormally high DNA stainability (HDS %) and round-head
sperms are elevated in idiopathic infertile men; this escalation is related
with cigarette smoking. These defects may be attributed to elevated oxidative stress and inadequate scavenging antioxidant enzymes in the
seminal fluid (Elshal et al. 2009). Later Niu et al. (2010) also reported that
smoking has adverse effects on the semen volume, sperm motility and
morphology and decreases sperm DNA integrity and nuclear maturation
of the smokers. Further, Ghaffari and Rostami (2013) reported that
spermatozoa consume adenosine triphosphate (ATP) rapidly. Creatine
kinase (CK), produced by creatine phosphate, is an energy reservoir for
the regeneration of ATP which play an important role in sperm motility.
They showed significantly lower sperm CK activity and motility in male
smokers. Smoking, by diminishing sperm CK activity, may potentially
impair sperm energy homeostasis which in turn affects sperm motility.
This can be an important mechanism that may cause infertility in male
smokers. Al-Matubsi et al. (2011) from Jordan also found that smokers
had significantly lower sperm concentration, motility and higher serum
testosterone and LH levels. Taha et al. (2012) observed that smoking
(cigarettes/day and duration) has unfavourable effects on sperm motility,
viability, DNA fragmentation, seminal zinc levels, and semen reactive
oxygen species levels, and it is directly correlated with cigarette quantity
and smoking duration. Smoking leads to a significant decline in semen
quality and elevated number of leukocytes, thus smoking may affect
the fertilization efficiency (Zhang et al. 2013). These data suggest that
tobacco smoking is harmful to male reproductive health by reducing
sperm count, concentration, motility, viability etc enhancing sperm DNA
fragmentation, sperm head shape abnormality etc.

In addition to tobacco smoking, tobacco chewing may also affect the
male reproduction. Sunanda et al. (2014) reported the adverse impact of
tobacco chewing on semen parameters which was obvious even with mild
chewers, but with the intensive chewing habits phenotypes of sperms,
defects in the head and cytoplasmic residue were drastically affected.
Recently, Patel et al. (2015) also observed an inverse dose–response
relationship between tobacco chewing and semen volume, total sperm
count, viable and motile sperm percentage. Heavy or long-term tobacco
chewers had a lower sperm concentration. Kumar (2013) reviewed the
data on tobacco and areca nut chewing with regards to and reproductive
impairments and mentioned that that smokeless tobacco use is also
harmful as smoking for reproduction and use of areca nut might have
further compounded the problem. Recently Choksi et al. (2015) also
reported that smoking and tobacco chewing deteriorate the sperm quality
which in turn leads to infertility of the male partners. They concluded that
lifestyle modification can help the couples to conceive spontaneously or
improve conception with ART treatment. Kumar et al. (2014) studied the
role of various lifestyle and environmental factors in male reproduction
and their association with respect to semen quality, increased oxidative
stress as well as sperm DNA damage. They found significant variation in
semen quality parameter between lifestyle and environmental exposed
and non-exposed subjects. Further, the levels of antioxidants were
reduced, and sperm DNA damage was higher among the lifestyle and/or
environmental exposed subjects, though the changes were not significant.
They concluded that various lifestyle factors such as tobacco smoking,
chewing and alcohol use as well as exposure to toxic agents might be
attributed to the risk of deteriorating semen quality and elevation in
oxidative stress and sperm DNA damage.

Alcohol/caffine
Alcohol is one of the top three addictives substances and humans
are using extensively since long time in all over the world. La Vignera
et al. (2013) mentioned that although alcohol is widely used, its impact
on the male reproductive function is still controversial. They reviewed
clinical studies and concluded that alcohol consumption is associated
with a deterioration of sperm parameters which may be partially
reversible after alcohol consumption discontinued. Earlier, Stutz et al.
(2004) examined the effects of alcohol, tobacco, and drug use on plasma
testosterone and seminal characteristic. Alcohol and tobacco use were
associated significantly; subjects who used these substances exhibited a
nonsignificant reduction in sperm concentration, viability, motility, and
normal morphology. There was a significant decrease in sperm motility
those used moderate amounts of aspirin. However, Jensen et al. (2014)
found no consistent association between any semen variable and alcohol
consumption, either for total consumption or consumption by type of
alcohol. However, they found a linear association between total alcohol
consumption and total or free testosterone level. Alcohol intake was
not significantly associated with serum inhibin B, LH or FSH levels in
either group. Gaur et al. (2010) reported that alcohol abuse targets sperm
production and morphology and smoke-induced toxins mainly hamper
sperm motility as well as seminal fluid quality. Progressive worsening
in semen quality is related to quantity of alcohol intake and cigarettes
smoked. Earlier, Kumar et al. (1992) reports adverse effects of smokedried
meat extract (SME) on sperm morphology of Swiss mice which was
dose dependent.

Caffeine is a widely consumed substance and consumption of caffeine
is increasing in recent years among youth as an energetic drink. Drinking
too much coffee can reduce a man’s ability to become father. Jensen et al.

(2010) reported that higher cola and/or caffeine intake was associated with
reduced sperm concentration and total sperm count which was significant
for cola. Recently Dias et al. (2015) hypothesized that caffeine changes
human Sertoli cells (hSCs) metabolism as well as oxidative profile, which
are vital for spermatogenesis. They reported that moderate consumption
of caffeine appears to be safe to male reproductive health since it
encourages lactate production by SCs, which can stimulate germ cells
survival. Nevertheless, precaution should be taken by heavy consumers
of beverages and food complemented with caffeine to avoid deleterious
effects in hSCs functioning. Ramlau-Hansen et al. (2008) studied the
relationship between prenatal and current caffeine exposure and semen
quality. There was a tendency toward declining semen volume and mean
testosterone and inhibin B concentrations with increasing maternal coffee
drinking during pregnancy. Sons of mothers drinking (4-7 cups/day)
had lower testosterone levels with respect to sons of mothers drinking
0-3 cups/day. They mentioned that the results are tentative, but they do
not exclude a small to moderate effect of prenatal coffee consumption on
semen volume and reproductive hormones. Present adult caffeine intake
did not show any clear relations with semen quality, but high caffeine
intake related to a higher testosterone concentration.

There are reports on the influence of caffeine on movement
characteristics, fertilizing capacity of human spermatozoa. Earlier Aitken et
al. (1983) reported that caffeine treatment to frozen-thawed human semen
induced a significant rise in the number of motile spermatozoa but did
not impact the quality of movement. Caffeine treatment of frozen-thawed
human spermatozoa also augmented the percentage of spermatozoa
penetrating cervical mucus membrane, by elevating the frequency
rather than the accomplishment of collisions between spermatozoa and
the cervical mucus interface. A preliminary report on the effect of the
addition of caffeine to frozen sperms indicated that the addition of 7.2
mM caffeine proved optimal and resulted in 40% to 80% amplified sperm
motility (Barkay et al., 1977). Later they carried out a study to determine
the impact of caffeine on the fertilizing capacity of sperm cell. Sixty
women underwent artificial insemination by donor with frozen/thawed
semen, with or without addition of caffeine. Fourteen women became
pregnant among caffeine-treated semen, whereas only seven pregnancies
occurred among women received semen without caffeine during the six
months period. Thus, they concluded that in vitro caffeine treatment of
fertile donor semen does not damage the spermatozoa; however, it seems
to improve the fertilizing capacity (Barkay et al., 1984). Further, Makler
et al. (1980) also reported that caffeine increased the percentage of motile
spermatozoa by 30% to 50% in approximately two-thirds of cases but
no influence on sperm velocity was detected. Further, it was found that
nonmotile live spermatozoa were activated by caffeine.

Obesity/ Physical activity/sedentary life
Obesity is a condition in which additional body fat gets accumulated
and has been associated with an elevated risk of many diseases such as
cardiovascular diseases, diabetes mellitus and certain types of cancer
(Visscher and Seidell, 2001). The increasing prevalence of obesity around
the world in recent decades can be explain by using high caloric foods,
sedentary work, no or little exercise and even using vehicle for short
distances, along with use of modern technologies that reduce the need for
physical activity etc. It is gradually recognizing that obesity is one of the
causes of sub fertility. The male infertility increased worldwide, which also
coinciding with the high occurrence of obesity. There is a report which
indicated that sperm concentration was significantly lower in the obese
group as compared to the group with BMI 17-20, 20-25 and 25-30 kg/m2 (Koloszar et al., 2005). Kort et al. (2006) found that men with a BMI greater
than 25 kg/m2 have fewer chromatin-intact normal-motile sperm cells per
ejaculate as well as total number of normal-motile sperm cells. Therefore,
to ensure maximum fertility potential, patients may be advised to reduce
body weight. BMI was positively connected to estradiol levels and inversely
to total testosterone and sex hormone-binding glogulin levels (Chavarro
et al. 2009). They also reported a strong inverse relationship between BMI
and inhibin B levels and a lower testosterone: LH ratio among subjects
with a BMI ≥35 kg/m2. Further, BMI was unrelated to sperm motility,
concentration, or morphology. In addition, there was steady decline in
ejaculate volume with increasing BMI. Further, men with BMI ≥35 kg/m2
had a lower sperm count than normal weight men and sperm with high
DNA damage were significantly more in obese men.

A negative association between BMI and neutral alpha-glucosidase
levels, motility, rapid motility, and a positive relationship between BMI and
seminal fructose levels was reported. No associations were found between
BMI and sperm concentration. The study supports a deleterious effect of
obesity on seminal quality, probably by alterations in the function of the
epididymis (Martini et al. 2010). Later Hajshafiha et al. (2013) found that
obese men were found to be 3.5 times more likely to have oligospermia.
BMI was not connected with mean numeric values of the semen-analysis
parameters, including sperm count, motility and morphology. BMI was
not also significantly associated with hormone such as LH, prolactin,
and LH/FSH ratio. However, a significant relationship was observed
between BMI and estradiol, sex hormone-binding globulin, and the
testosterone/estradiol ratio. Eisenberg et al. (2014) also reported that body
size (measured by BMI or waist ircumference) is negatively related with
semen parameters with little influence of physical activity. They further
suggested that considering worldwide obesity prevalent, further study of
the role of weight loss to improve semen quality is needed. Du Plessis et
al. (2010) reviewed the data on obesity and male infertility and pointed to
an augmented likelihood of abnormal semen quality among obese, and an
elevated risk for subfertility among couples if male partner is obese. Several
mechanisms might be resposible for the role of obesity on male infertility,
by inducing sleep apnea, increased scrotal temperatures, alterations
in hormonal profiles, decline sperm quality. They further, mentioned
that neither the reversibility of obesity-associated male infertility with
weight loss nor effective therapeutic interventions have been studied
thoroughly. However, MacDonald et al. (2010) could not find evidence of
an association between increased BMI and semen parameters based upon
a systematic review with meta-analysis. They described limitation of the
review was that data from most of the studies could not be aggregated for
meta-analysis. Recently Shukla et al. (2014) mentioned that obesity has
been linked to male fertility because of lifestyle changes, internal hormonal
environment variations, and sperm genetic factors. They also mentioned
that there are emerging evidences that obesity negatively affects male
reproductive potential not only by decreasing sperm quality, but it affects the molecular structure of germ cells in the testes and eventually affects
the sperm cells maturity and function. They also reported that the miRNA
profile is changed in spermatozoa of obese; however, the effect of these
alterations in fertilization and embryo health is not yet fully known.

Recently Chiu et al. (2014) studied the relationship between
consumption of sugar-sweetened beverages (SSB) and semen quality.
They found higher concentration of SSB was associated with lower sperm
motility among healthy men. This might be associated with weight gain
with respect to the high intake of SSB. Earlier studies have showed that
high intake of SSBs cause weight gain and obesity (Ebbeling et al., 2012;
Pan et al., 2013). Recently Guo et al. (2017) found standardized weighted mean differences (SMD) in sperm parameters (total sperm count, sperm
concentration, and semen volume) of abnormal weight groups decreased
to different degree compared to normal weight. Dose-response analysis
found SMD of sperm count, sperm concentration and semen volume
respectively fell 2.4%, 1.3% and 2.0% compared with normal weight for
every 5-unit increase in BMI. This systematic review with meta-analysis
has confirmed relationship between BMI and sperm quality, suggesting
obesity may be a detrimental factor of male infertility.

Drugs use or Abuse
In addition to the illicit drug abuse, some of the other drugs may also
affect human reproduction. Chronic medication can play a significant role
in the pathogenesis of male reproductive health and some of the drugs/
compounds may reach to the seminal plasma affecting semen quality. The
drugs that may distress male sexual health include drugs of abuse, central
nervous system depressants, antihypertensives, anticholinergics, and
psychotherapeutics agents (Wilson, 1991) and some anti-neoplastic drugs
also. The immediate effects of some of drugs therapy and its reversibility are
most readily observed in post-pubertal patients, but some antineoplastic
treatments can bring permanent azoospermia. The probability of
azoospermia is might be related to the agents and doses. The most hurtful
are alkylating agents (chlorambucil, procarbazine, cyclophosphamide,
melphalan, and busulfan), cisplatin and radiation (Meistrich, 2009).
Later Fronczak et al. (2012) reviewed the literature on insults of illicit
drug use on male fertility and reported that anabolic-androgenic steroids,
marijuana, cocaine, methamphetamines, and opioid narcotics, negatively
effect male fertility, and alterations in hypothalamic –pituitary-testicular
axis, sperm function and testicular structure. Earlier Holma (1977)
studied the effect of the oral administration of metandienone, an anabolic
steroid, on spermatogenesis in male athletes. The sperm density declined
46% after 1 month of use and 73% declined after 2 months with highly
pathologic sperms. The percentage of motile sperms diminished to
about 30% after two months of use. Further, seminal acid phosphatase
activity was markedly reduced after two months, while semen fructose
was markedly changed after one month of use. The observed changes
were reversable after discontinuation. Later, Turek et al. (1995) reported
that a bodybuilder with a five-year of steroid use led to azoospermic and
underwent successful gonadotropin replacement and conception was
achieved three months after therapy was initiated.

Recently El Osta et al. (2016) reported that substance abuse, including
anabolic-androgenic steroids (AAS), is commonly associated with
impairment of male reproductive function, through different pathways.
Earlier Moretti et al. (2007) also reported that azoospermia may be related
to the use of androgenic anabolic steroids. They reported azoospermic
case that had abused androgenic anabolic steroids and recovered
spermatogenesis six months after cessation of abuse and on hormonal
therapy. This endorses the recovery of spermatogenesis and suggests a
possible relationship between altered meiotic segregation and androgenic
anabolic steroids. Torres-Calleja et al. (2001) conducted a study to find
out the effect of androgenic anabolic steroids (AAS) on endocrine and
semen parameters of body builders. In subjects using AAS, eight had
lower sperm counts, three had azoospermia, two polyzoospermia, and
two had normal sperm counts. The percentage of morphologically normal
sperm was declined significantly, only 17.7% had normal spermatozoa.
Whereas, only one subject was found to be oligozoospermic in control
group. Recently McBride and Coward (2016) reported that both AAS and
testosterone replacement therapy (TRT) can depress the hypothalamicpituitary-
gonadal axis resulting in diminution of spermatogenesis. TRT or AAS cessation may result in spontaneous recovery of normal
spermatogenesis. However, some patients may not recover.

Psychosocial stress
Human feel different forms of stress, including psychological and
work stress, these can affect male fertility and reproduction. The social
and familial issues regarding reproduction are of great importance and
unnecessaty causes the stress. Earlier McGrady (1984) reported that mildto-
severe emotional stress depresses testosterone and perhaps interferes
with spermatogenesis in the human male. It is difficult to attribute
individual cases of infertility to psychological factors without evidence of
psychopathology. In animals social stress, high altitude, immobilization
stress and surgery, affect body weight, testosterone, copulatory behavior
and testicular morphology. Stress applied to the pregnant rat also affects
the sexual behavior and development of the male offspring. Hjollund et
al. (2004a) collected prospective data on job strain, and coorelated with
semen quality and probability of conceiving a clinical pregnancy and
found psychologic job strain encountered in normal jobs does not seem
to affect male reproductive function. Zorn et al. (2008) evaluated whether
psychological factors in males affect semen quality and pregnancy.
Possible depression in males is related to decreased sperm concentration,
and poor managing with stress is associated with elevated occurrence of
early miscarriage. Stress was correlated negatively with semen measures
of volume and percent normal morphologic forms (Giblin et al., 1988).
The data are consistent with the hypothesis that psychosocial stress
contributes significantly to the etiology of some forms of infertility
(Wasser et al., 1993). Gollenberg et al. (2010) examined the association
between stressful life events and semen quality and found that stressful
life events associated with diminishing semen quality in fertile men. The
experience of psychosocial stress may be a modifiable factor to prevent
the development of idiopathic infertility. Li et al. (2011) reviewed thirteen
socio-psycho-behavioral factors in 57 cross-sectional studies with 29,914
participants from 26 countries/regions. They found that psychological stress can lower sperm density and sperm progressive motility and increase
abnormal sperm. They further suggested that higher age, smoking, alcohol
consumption, and psychological stress were the risk factors for semen
quality. Further, health programs focusing on lifestyle and psychological
health would be helpful for male reproductive health. Earlier, Schneid-
Kofman and Sheiner (2005) also reviewed the relationship between
psychological stress and male infertility. They mentioned that most of
the studies rejected the theory of stress as a lone factor in infertility, but
stress stands as an additional risk factor for infertility. Later Collodel
et al. (2008) reported that stress seem to induce meiotic and structural
alterations in sperm cells. The spermatogenic process was improved after
a cycle of Conveyer of Modulating Radiance therapy showed that stress is
an extra risk factor for idiopathic infertility.

Recently, Nargund (2015) mentioned that numerous clinical studies
on psychological stress on male fertility have shown that stress is associated
with reduced fatherhood and abnormal semen characrtersic. Adequate
scientific evidence exists which suggest that psychological stress could
affect spermatogenesis. The hypothalamic–pituitary–adrenal axis has a
straight inhibitory action on the hypothalamic–pituitary–gonadal (HPG)
axis and Leydig cells. Inhibition of the HPG axis results in a decrease of
testosterone levels, which causes deviations in Sertoli cells and the blood–
testis barrier, leading to the seizure of spermatogenesis. Germ cells also
become vulnerable to gonadotoxins and oxidation. They concluded that
even though some limitation stress as a causative factor in male infertility
cannot be ignored. Earlier Wilson and Kopitzke (2002) concluded that there is a dearth of solid evidence that infertility patients demonstrate
more psychopathology than controls, and that there is modest evidence
for an association between distress during treatment and the outcome of
the treatment itself. Hjollund et al. (2004b) also conducted a prospective
study among Danish couples who were trying to become pregnant and
found no consistent associations between stress and serum concentration
of LH, FSH, inhibin B, testosterone, or estradiol. The effect of psychologic
stress associated with man’s daily life on semen quality is minor or
nonexistent. They reported that the effect of stress only on fecundability
among men with lower sperm concentration. Later Janevic et al. (2014)
evaluated associations between stressful life events, work-related stress
and perceived stress and semen quality. They found an inverse association
between perceived stress score and sperm concentration, motility, and
morphology. Further, men who experienced two or more stressful life
events had a lower percentage of motile sperm and morphologically
normal sperm compared with no stressful events. However, job strain was
not associated with semen quality.

There are few reports on psychological stress among men undergoing
IVF. Clarke et al. (1999) assessed psychological variables, including selfreported
stress, and sperm parameters. They demonstrated an inverse
relationship between semen quality and psychological stress among
subjects undergoing IVF. The emotional stress to a subject during IVF
program negatively affects the quality of semen provide evidence for a
significant decline in semen quality of male IVF patients at time of
egg retrival (Ragni and Caccamo 1992). Earlier, Harrison et al. (1987)
evaluated semen profiles of couples underwent IVF treatment. The semen
sample was collected at the time of pre-IVF workup, and the second one
was after ovum aspiration. The data revealed that total sperm count,
sperm density, and sperm motility were significantly lower in the second
sample compared to frist one for IVF.

Lifestyle factors such as tobacco smoking or chewing, alcohol, obesity,
and some of the illicit drugs like cannabis, cocaine, etc and extreme heat,
have harmful effects on male reproduction (Kumar et al., 2009). Further
the data on other factors such as use of mobile phone and stress on
reproductive health is also accumulated in recent decade. Some “negative
lifestyle factors” may be contributing to the growing trends in male
infertility. Further, occupational /environmental exposure to some of
the organic solvents, pesticides, metals, plasticizers especially phthalates;
ionizing and nonionizing radiations, extreme heat, stress etc. may be
associated with declining semen quality. There may not be conclusive
evidence for the entire lifestyle, occupational and environmental factors
discussed above but adopting healthy lifestyle and prevention of the usage
of reproductive toxicants may be beneficial at least in part in prevention
of infertility as well in pregnancy outcome. Sub-fertile and/or even
normal individuals have some control over their reproductive function by
adopting healthy lifestyles.

Acknowledgements

One of the authors (SK) is thankful to ICMR, DST, DBT, New Delhi,
for financial assistance in the form of adhoc research grants on various
aspects of reproductive health with respect to occupational, environmental
exposure and on smokeless tobacco use and health which form the author
foundation on this important issue of human reproduction.